Review

Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation

Plasminogen Kringle 5 is one of the most potent cytokines identified to inhibit the proliferation and migration of vascular endothelial cells. Herein, six aptamer candidates that specifically bind to Kringle 5 were generated by the systematic evolution of ligands by exponential enrichment (SELEX). After 10 rounds of screening against Kringle 5, a highly enriched ssDNA pool was sequenced and the representative aptamers were subjected to binding assays to evaluate their affinity and specificity. The preferred aptamer KG-4, which demonstrated a low dissociation constant (K_d) of ∼ 432 nM and excellent selectivity for Kringle 5. A conserved “motif” of eight bases located at the stem-loop intersection, common to the aptamer, was further confirmed as the recognition element for binding with Kringle 5. The bulge formed by the motif and depression on the lysine binding site of Kringle 5 were both located at the binding interface, and the “induced fit” between their structures played a central role in the recognition process. Kringle 5 interacts KG-4 primarily through enthalpy-driven van der Waals forces and hydrogen bond. The key nucleotides A34 and C35 at motif on KG-4 and the positively charged amino acids in the loop 1 and loop 4 regions on Kringle 5 play a major role in the interaction. Furthermore, KG-4 dose-dependently reduced the proliferation inhibition of vascular endothelial cells by Kringle 5 and had a blocking effect on the function of Kringle 5 in inhibiting migration and promoting apoptosis of vascular endothelial cells in vitro. This study put a new light on protein-aptamer binding mechanism and may provide insight into the treatment of ischemic diseases by target depletion of Kringle 5.

Pentraxin-3 (PTX3) is the prototype of the long pentraxin subfamily, an acute-phase protein consisting of a C-terminal pentraxin domain and a unique N-terminal domain. PTX3 was initially isolated from human umbilical vein endothelial cells and human FS-4 fibroblasts. It was subsequently found to be also produced by synoviocytes, chondrocytes, osteoblasts, smooth muscle cells, myeloid dendritic cells, epithelial cells, and tumor cells. Various modulatory factors, such as miRNAs, cytokines, drugs, and hypoxic conditions, could regulate the expression level of PTX3. PTX3 is essential in regulating innate immunity, inflammation, angiogenesis, and tissue remodeling. Besides, PTX3 may play dual (pro-tumor and anti-tumor) roles in oncogenesis. PTX3 is involved in the occurrence and development of many non-cancerous diseases, including COVID-19, and might be a potential biomarker indicating the prognosis, activity,and severity of diseases. In this review, we summarize and discuss the potential roles of PTX3 in the oncogenesis and pathogenesis of non-cancerous diseases and potential targeted therapies based on PTX3.

In this study, three molecules with distorted asymmetric D-A-D' structure were synthesized by one-step nucleophilic substitution reaction using different fluorophores (carbazole, phenoxazine, phenothiazine) as electron donors and benzophenone with distorted conformation as electron acceptor. The target compounds were all confirmed by ¹H NMR, ¹³C NMR and EI-MS. In addition, the molecular skeleton of the target compound containing a phenothiazine donor group was further confirmed by X-ray single-crystal diffraction analysis. Combined with the results of UV–vis absorption spectra and fluorescence emission spectra, we found that the different electron donating ability of donor parts (carbazole, phenoxazine and phenothiazine) led to the blue, green and light yellow fluorescence of these compounds in the solid states. Subsequent studies showed that these three compounds all showed remarkable solvatochromism in different organic solvent due to the intramolecular charge transfer (ICT) effect, and the increase of solvent polarity induces a red-shift in the emission wavelength. The results of mechanochromic properties confirmed that only the compound containing phenothiazine fluorophore showed obvious reversible mechanochromic properties. Compounds containing carbazole and phenothiazine groups showed aggregation-induced enhanced emission (AIEE), while compound bearing phenoxazine showed typical aggregation-induced emission (AIE) behavior. Through powder X-ray diffraction (XRD) analysis experiment, crystal structure analysis and theoretical calculation, the relationship between the structure and properties of these molecules was discussed. Finally, we also preliminarily explored the application of these molecules in biological imaging, which exhibited excellent biocompatibility and cell permeability in living cells. In brief, through reasonable molecular design, the luminescent properties and solvatochromism properties of these compounds can be regulated, which provides a theoretical basis for the rational design of molecules with excellent photophysical properties.

Uncontrolled tumor growth and subsequent distant metastasis are highly dependent on an adequate nutrient supply from tumor blood vessels, which have relatively different pathophysiological characteristics from those of normal vasculature. Obviously, strategies targeting tumor vasculature, such as anti-angiogenic drugs and vascular disrupting agents, are attractive methods for cancer therapy. However, the off-target effects and high dose administration of these drug regimens critically restrict their clinical applications. In recent years, nanomedicines focused on tumor vasculature have been shown to be superior to traditional therapeutic methods and do not induce side effects. This review will first highlight the recent development of tumor vasculature-targeting nanomedicines from the following four aspects: 1) angiogenesis-inhibiting nanomedicines (AINs); 2) vasculature-disrupting nanomedicines (VDNs); 3) vasculature infarction nanomedicines (VINs); and 4) vasculature-regulating nanomedicines (VRNs). Furthermore, the design principles, limitations, and future directions are also discussed.

Based on the essential roles of tumor blood vessels, the therapeutic strategies targeting tumor vasculature have exhibited good clinical therapeutic outcomes. However, poor patient adherence to free drug administration limits their clinical usage. Nanomedicines have great potential to overcome the abovementioned obstacle. This review summarizes the tumor-vasculature targeting nanomedicines from four aspects: 1) angiogenesis-inhibiting nanomedicines (AINs); 2) vasculature-disrupting nanomedicines (VDNs); 3) vasculature infarction nanomedicines (VINs); and 4) vasculature regulating nanomedicines (VRNs). In addition, this review provides perspectives on this research field.

The development of biological technologies in genomics, proteomics, and bioinformatics has led to the identification and characterization of the complete set of coding genes and their roles in various cellular pathways in cancer. Nevertheless, the cellular pathways have not been fully figured out like a jigsaw puzzle with missing pieces. The discovery of noncoding RNAs including microRNAs (miRNAs) has provided the missing pieces of the cellular pathways. Likewise, miRNAs have settled many questions of inexplicable patches in the endoplasmic reticulum (ER) stress pathways. The ER stress-caused pathways typified by the unfolded protein response (UPR) are pivotal processes for cellular homeostasis and survival, rectifying uncontrolled proteostasis and determining the cell fate. Although various factors and pathways have been studied and characterized, the understanding of the ER stress requires more wedges to fill the cracks of knowledge about the ER stress pathways. Moreover, the roles of the ER stress and UPR are still controversial in cancer despite their strong potential to promote cancer. The noncoding RNAs, in particular, miRNAs aid in a better understanding of the ER stress and its role in cancer. In this review, miRNAs that are the more-investigated subtype of noncoding RNAs are focused on the interpretation of the ER stress in cancer, following the introduction of miRNA and ER stress.